Understanding immunosuppressants

UC has inflammation within the large intestine that is caused by our immune system. With the first class of UC medications, mesalamine/5ASA (lialda/asacol), is an anti-inflammatory compound. The second and third classes of UC medications directly go after the immune system itself by weaking its response.

When the immune system attacks, it produces a lot of WBC and sends them to the attack site. WBC directly cause inflammation within the body. If you've ever had a Complete Bloodcell Count (CBC) blood test while flaring (common) then your WBC count should be incredibly high and well above normal ranges on your test. Immunomodulators (imuran/azathioprine or 6MP) intentionally reduce the amount of WBC that your immune system can create, the less WBC you have within your veins, the less formidable of an attack your immune system can create and the better your UC symptoms get. Immunomodulators work by slowing the rate in which your immune system is capable of producing WBC, the slower the pace the less you can have at any one time.

Biologics work by interfering with your immune system's ability to signal, initiate, and complete an attack. The immune system produces a series of messenger proteins that say "hey send an attack over here" which is known as a tnf-alpha protein. Remicade, humira, and simponi are tnf-alpha-blockers, which muffle or mute the immune system's ability to call for an attack. The quieter the battle cry for an attack, the less formitable of an attack the immune system can initiate.

Uceris is 90 percent topical and 10 percent systematic, so yes you can experience side effects from it. Any predominantly topical medication that hits the large intestine is absorbed about 10 percent. That's because the intestine is lined with tiny blood vessels known as capilaries near the surface, which readily circulate that medication throughout the body: uceris, mesalamine like lialda, steroid enemas, suppositories or foams are all examples.

One tnf-alpha protein joins with one remicade protein and they become inert, and they both are excreted from the body without without causing inflammation in that one instance (normal clearance of blood molecules from the body, through stool I believe). An infusion of a biologic includes millions of such anti-tnf-alpha proteins. You just don't want to runout between doses.

I don't know the workings of tnf-alpha in any greater detail than that (but I'm sure ypu can Google it), it's a messenger protein distributed through the circulatory system and received and responded to with WBC. Certainly it's systematic, as we're talking circulatory system. I've never experienced a side effect after 3.5 years plus, but I did achieve a remission.

The Crohn's and Colitis Foundation of America has some great info on the risks versus benefits of immunomodulators and biologics that puts odds to side effects. about 65 percent of UC patients receive a response and less than 1 percent experience side effects.

Webcast: programs.rmei.com/CCFA139VL/presentation/player.html
Transcript: http://www.ccfa.org/assets/pdfs/risk-and-benefits-transcript.pdf

iPoop said...
Uceris is 90 percent topical and 10 percent systematic, so yes you can experience side effects from it. Any predominantly topical medication that hits the large intestine is absorbed about 10 percent. That's because the intestine is lined with tiny blood vessels known as capilaries near the surface, which readily circulate that medication throughout the body: uceris, mesalamine like lialda, steroid enemas, suppositories or foams are all examples.

My understanding is that the steroid budesonide in Uceris and Entocort is almost fully absorbed by the bowel wall. It then travels to the liver via the hepatic portal vein. Once in the liver, it is approximately 90% metabolized on this first trip through the liver, with the remaining approximate 10% of the steroid passing through the liver intact and entering the blood stream and traveling to other places in the body. It will later on circulate back to the liver and get metabolized further, and repeat, until it's gone.

In other words, your numbers are about right but your explanation isn't. Budesonide is said to have a high "first pass metabolism," meaning the liver metabolizes most of it on the 'first pass' through the liver, before it could go elsewhere in the body.

Some people's livers metabolize less than 90% on the first pass through, meaning more than 10% enters the bloodstream. That's probably why some people get more side effects. Some people's livers metabolize more than 90% on the first pass through. They probably get very little side effects. But 90% is a 'typical' liver response.

That's my understanding based on what a PharmD explained.

Thank you ipoop, that makes a lot of sense. I suppose my next question, if you don't mind, is what is done by the damage left behind from the chronic inflammation? I assume the inflammation leaves the colon damaged (friable?), so how does the body heal that area of the immune response is limited?

I just watched the video from the Crain's and Colitis Foundation with Dr. Siegle. It was very well done and worth watching.

I now feel like I have a much better understanding of the risks of lymphoma and serious infection on these drugs. They do seem rather low.

Two issues he doesn't address are hair loss and weight gain on methotrexate.

I thought it was interesting that he fielded a question from one person who said he got a serious infection directly after getting on Remicade. Now, maybe he was drawn to the forum because he was one of the unlucky ones. But, with rates of five in 10,000, it seems odd that one of those five were one of his questioners.

It was also interesting that he answered a question about Naltrexone.

I know that the Briggs Protocol calls for using Wellbutrin.

There's so much to learn. I want to know as much as I can before my appointment with my new gastro at the end of the month.